Prenatal cerebral ischemia triggers dysmaturation of caudate projection neurons

Evelyn McClendon, Kevin Chen, Xi Gong, Elica Sharifnia, Matthew Hagen, Victor Cai, Daniel C. Shaver, Art Riddle, Justin M. Dean, Alistair J. Gunn, Claudia Mohr, Joshua S. Kaplan, David J. Rossi, Christopher (Chris) Kroenke, Alan (Roger) Hohimer, Stephen Back

Research output: Contribution to journalArticle

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Abstract

Objective Recently, we reported that the neocortex displays impaired growth after transient cerebral hypoxia-ischemia (HI) at preterm gestation that is unrelated to neuronal death but is associated with decreased dendritic arbor complexity of cortical projection neurons. We hypothesized that these morphological changes constituted part of a more widespread neuronal dysmaturation response to HI in the caudate nucleus (CN), which contributes to motor and cognitive disability in preterm survivors. Methods Ex vivo magnetic resonance imaging (MRI), immunohistochemistry, and Golgi staining defined CN growth, cell death, proliferation, and dendritic maturation in preterm fetal sheep 4 weeks after HI. Patch-clamp recording was used to analyze glutamatergic synaptic currents in CN neurons. Results MRI-defined growth of the CN was reduced after ischemia compared to controls. However, no significant acute or delayed neuronal death was seen in the CN or white matter. Nor was there significant loss of calbindin-positive medium spiny projection neurons (MSNs) or CN interneurons expressing somatostatin, calretinin, parvalbumin, or tyrosine hydroxylase. Morphologically, ischemic MSNs showed a markedly immature dendritic arbor, with fewer dendritic branches, nodes, endings, and spines. The magnitude and kinetics of synaptic currents, and the relative contribution of glutamate receptor subtypes in the CN were significantly altered. Interpretation The marked MSN dendritic and functional abnormalities after preterm cerebral HI, despite the marked resistance of immature CN neurons to cell death, are consistent with widespread susceptibility of projection neurons to HI-induced dysmaturation. These global disturbances in dendritic maturation and glutamatergic synaptic transmission suggest a new mechanism for long-term motor and behavioral disabilities in preterm survivors via widespread disruption of neuronal connectivity. Ann Neurol 2014;75:508-524

Original languageEnglish (US)
Pages (from-to)508-524
Number of pages17
JournalAnnals of Neurology
Volume75
Issue number4
DOIs
StatePublished - 2014

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Caudate Nucleus
Brain Ischemia
Neurons
Ischemia
Brain Hypoxia-Ischemia
Cell Death
Growth
Magnetic Resonance Imaging
Calbindin 2
Calbindins
Parvalbumins
Neocortex
Transient Ischemic Attack
Glutamate Receptors
Tyrosine 3-Monooxygenase
Interneurons
Somatostatin
Synaptic Transmission
Sheep
Spine

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

McClendon, E., Chen, K., Gong, X., Sharifnia, E., Hagen, M., Cai, V., ... Back, S. (2014). Prenatal cerebral ischemia triggers dysmaturation of caudate projection neurons. Annals of Neurology, 75(4), 508-524. https://doi.org/10.1002/ana.24100

Prenatal cerebral ischemia triggers dysmaturation of caudate projection neurons. / McClendon, Evelyn; Chen, Kevin; Gong, Xi; Sharifnia, Elica; Hagen, Matthew; Cai, Victor; Shaver, Daniel C.; Riddle, Art; Dean, Justin M.; Gunn, Alistair J.; Mohr, Claudia; Kaplan, Joshua S.; Rossi, David J.; Kroenke, Christopher (Chris); Hohimer, Alan (Roger); Back, Stephen.

In: Annals of Neurology, Vol. 75, No. 4, 2014, p. 508-524.

Research output: Contribution to journalArticle

McClendon, E, Chen, K, Gong, X, Sharifnia, E, Hagen, M, Cai, V, Shaver, DC, Riddle, A, Dean, JM, Gunn, AJ, Mohr, C, Kaplan, JS, Rossi, DJ, Kroenke, CC, Hohimer, AR & Back, S 2014, 'Prenatal cerebral ischemia triggers dysmaturation of caudate projection neurons', Annals of Neurology, vol. 75, no. 4, pp. 508-524. https://doi.org/10.1002/ana.24100
McClendon E, Chen K, Gong X, Sharifnia E, Hagen M, Cai V et al. Prenatal cerebral ischemia triggers dysmaturation of caudate projection neurons. Annals of Neurology. 2014;75(4):508-524. https://doi.org/10.1002/ana.24100
McClendon, Evelyn ; Chen, Kevin ; Gong, Xi ; Sharifnia, Elica ; Hagen, Matthew ; Cai, Victor ; Shaver, Daniel C. ; Riddle, Art ; Dean, Justin M. ; Gunn, Alistair J. ; Mohr, Claudia ; Kaplan, Joshua S. ; Rossi, David J. ; Kroenke, Christopher (Chris) ; Hohimer, Alan (Roger) ; Back, Stephen. / Prenatal cerebral ischemia triggers dysmaturation of caudate projection neurons. In: Annals of Neurology. 2014 ; Vol. 75, No. 4. pp. 508-524.
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abstract = "Objective Recently, we reported that the neocortex displays impaired growth after transient cerebral hypoxia-ischemia (HI) at preterm gestation that is unrelated to neuronal death but is associated with decreased dendritic arbor complexity of cortical projection neurons. We hypothesized that these morphological changes constituted part of a more widespread neuronal dysmaturation response to HI in the caudate nucleus (CN), which contributes to motor and cognitive disability in preterm survivors. Methods Ex vivo magnetic resonance imaging (MRI), immunohistochemistry, and Golgi staining defined CN growth, cell death, proliferation, and dendritic maturation in preterm fetal sheep 4 weeks after HI. Patch-clamp recording was used to analyze glutamatergic synaptic currents in CN neurons. Results MRI-defined growth of the CN was reduced after ischemia compared to controls. However, no significant acute or delayed neuronal death was seen in the CN or white matter. Nor was there significant loss of calbindin-positive medium spiny projection neurons (MSNs) or CN interneurons expressing somatostatin, calretinin, parvalbumin, or tyrosine hydroxylase. Morphologically, ischemic MSNs showed a markedly immature dendritic arbor, with fewer dendritic branches, nodes, endings, and spines. The magnitude and kinetics of synaptic currents, and the relative contribution of glutamate receptor subtypes in the CN were significantly altered. Interpretation The marked MSN dendritic and functional abnormalities after preterm cerebral HI, despite the marked resistance of immature CN neurons to cell death, are consistent with widespread susceptibility of projection neurons to HI-induced dysmaturation. These global disturbances in dendritic maturation and glutamatergic synaptic transmission suggest a new mechanism for long-term motor and behavioral disabilities in preterm survivors via widespread disruption of neuronal connectivity. Ann Neurol 2014;75:508-524",
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AU - McClendon, Evelyn

AU - Chen, Kevin

AU - Gong, Xi

AU - Sharifnia, Elica

AU - Hagen, Matthew

AU - Cai, Victor

AU - Shaver, Daniel C.

AU - Riddle, Art

AU - Dean, Justin M.

AU - Gunn, Alistair J.

AU - Mohr, Claudia

AU - Kaplan, Joshua S.

AU - Rossi, David J.

AU - Kroenke, Christopher (Chris)

AU - Hohimer, Alan (Roger)

AU - Back, Stephen

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N2 - Objective Recently, we reported that the neocortex displays impaired growth after transient cerebral hypoxia-ischemia (HI) at preterm gestation that is unrelated to neuronal death but is associated with decreased dendritic arbor complexity of cortical projection neurons. We hypothesized that these morphological changes constituted part of a more widespread neuronal dysmaturation response to HI in the caudate nucleus (CN), which contributes to motor and cognitive disability in preterm survivors. Methods Ex vivo magnetic resonance imaging (MRI), immunohistochemistry, and Golgi staining defined CN growth, cell death, proliferation, and dendritic maturation in preterm fetal sheep 4 weeks after HI. Patch-clamp recording was used to analyze glutamatergic synaptic currents in CN neurons. Results MRI-defined growth of the CN was reduced after ischemia compared to controls. However, no significant acute or delayed neuronal death was seen in the CN or white matter. Nor was there significant loss of calbindin-positive medium spiny projection neurons (MSNs) or CN interneurons expressing somatostatin, calretinin, parvalbumin, or tyrosine hydroxylase. Morphologically, ischemic MSNs showed a markedly immature dendritic arbor, with fewer dendritic branches, nodes, endings, and spines. The magnitude and kinetics of synaptic currents, and the relative contribution of glutamate receptor subtypes in the CN were significantly altered. Interpretation The marked MSN dendritic and functional abnormalities after preterm cerebral HI, despite the marked resistance of immature CN neurons to cell death, are consistent with widespread susceptibility of projection neurons to HI-induced dysmaturation. These global disturbances in dendritic maturation and glutamatergic synaptic transmission suggest a new mechanism for long-term motor and behavioral disabilities in preterm survivors via widespread disruption of neuronal connectivity. Ann Neurol 2014;75:508-524

AB - Objective Recently, we reported that the neocortex displays impaired growth after transient cerebral hypoxia-ischemia (HI) at preterm gestation that is unrelated to neuronal death but is associated with decreased dendritic arbor complexity of cortical projection neurons. We hypothesized that these morphological changes constituted part of a more widespread neuronal dysmaturation response to HI in the caudate nucleus (CN), which contributes to motor and cognitive disability in preterm survivors. Methods Ex vivo magnetic resonance imaging (MRI), immunohistochemistry, and Golgi staining defined CN growth, cell death, proliferation, and dendritic maturation in preterm fetal sheep 4 weeks after HI. Patch-clamp recording was used to analyze glutamatergic synaptic currents in CN neurons. Results MRI-defined growth of the CN was reduced after ischemia compared to controls. However, no significant acute or delayed neuronal death was seen in the CN or white matter. Nor was there significant loss of calbindin-positive medium spiny projection neurons (MSNs) or CN interneurons expressing somatostatin, calretinin, parvalbumin, or tyrosine hydroxylase. Morphologically, ischemic MSNs showed a markedly immature dendritic arbor, with fewer dendritic branches, nodes, endings, and spines. The magnitude and kinetics of synaptic currents, and the relative contribution of glutamate receptor subtypes in the CN were significantly altered. Interpretation The marked MSN dendritic and functional abnormalities after preterm cerebral HI, despite the marked resistance of immature CN neurons to cell death, are consistent with widespread susceptibility of projection neurons to HI-induced dysmaturation. These global disturbances in dendritic maturation and glutamatergic synaptic transmission suggest a new mechanism for long-term motor and behavioral disabilities in preterm survivors via widespread disruption of neuronal connectivity. Ann Neurol 2014;75:508-524

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